DESCRIPTION: (Principal Investigator's) Hollow tubular structures with specific internal diameters have attracted a great deal of attention lately due to their potential utility in chemistry, biology, and materials science. Recently, we reported a new class of tubular structures, based on the self-assembly of cyclic peptide subunits, termed "organic nanotubes", that has shown promising utility in chemical and biological settings. Here, we proposed to continue our studies in the fundamental design, characterization, and use of peptide tubular assemblies in biologically relevant channel-mediated processes. The proposed research program is divided into two main sections. The first section deals with the fundamental aspects of design, synthesis, and characterization of molecular assemblies for the study of various aspects of selective pore-mediated transport of ions and small hydrophilic molecules across lipid bilayers. The scope of these studies range from the design and solution-phase characterization of model cylindrical ensembles aimed at probing the molecular recognition/inclusion propensities of appropriately designed structures to the design and functional characterization of ligand-gated transmembrane tubular assemblies. The second section deals mainly with the biological applications of the peptide nanotube systems and the ability to form channel and pore structures in living cell membranes. Specifically it builds upon our recent encouraging results in both the rational as well as combinatorial cyclic peptide library approaches toward the design/discovery of a new generation of target-selective antimicrobial and cytotoxic agents. It is our hope that the research program proposed here will bring us closer to achieving our long term goal aimed at the design of novel drug delivery vehicles and the design of a new class of selective and potent antimicrobial and cytotoxic agents. The specific aims of the proposed research are: (1) Design, synthesis, and characterization of covalently constrained water soluble peptide cylinders for use in the study of molecular recognition and inclusion of hydrophilic agents; (2) Study the scope and the selectivity of channel-mediated molecular transport in self-assembled membrane channel structures; (3) Design and functionally characterize ion-gated transmembrane channel structures using a variety of techniques including single channel conductance measurements; (4) In vitro evaluation of the cytotoxicity profiles of channel and pore forming peptide structures, selected through directed as well as a combinatorial peptide library approaches, against a variety of bacterial strains, fungi, and normal and malignant mammalian cell lines; (5) Rational design and biological evaluation of cell-type specific cytotoxic agents; (6) Selection and discovery of cell-type specific cytotoxic agents through combinatorial libraries of transmembrane channel forming peptides.